The etiologies of many human neoplasms (breast, pituitary, prostatic) involve poorly understood interactions between hormones and glandular epithelium. Advancement in our knowledge of the mechanisms underlying hormonal influences on carcinogenesis could lead to fuller understanding and better management of these diseases. We are investigating two animal model systems (Wistar/Lewis rats and C57 BL/6J mice) using pituitary primordia (Rathke's Pouch, RP)-derived tumors that appear to be excellent models for secretory neoplasms in general. Our experiments analyze the role of hormones in tumorigenesis and the relationship of the hormonal influences to specific stages of differentiation in the induced tissue. The importance of the site of RP implantation, and the effects of tissues associated with RP, on subsequent tumorigenesis are also analyzed. Microsurgically isolated fetal rat RP yield pituitary growths when transplanted either to kidney capsule (KC) or brain sites of adult hosts. Daily estradiol benzoate has stimulated tumorigenic transformation in our KC-implanted 12 day RP, but not from 15 day RP. These results have confirmed our earlier data on the tumor susceptibility of 12 day RP. Brain-implanted 12 day RP have developed pituitary tumors that appear to be site-dependent. Close proximity of an RP implant to a brain ventricular surface appears to inhibit the development of pituitary growths. Implantation to the hypothalamus, lateral arcuate region, appears to stimulate pituitary growth. Pilot studies using C57 BL/6J mice reveal an extremely high incidence of large pituitary tumors in females in this strain. These tumors are active secretory tumors and preliminary data indicate that their development is endocrine dependent. Pilot studies have ascertained that our microsurgical techniques can be applied to these mice. In this research proposal we delineate our plans for further characterization of hormonal influences on these RP-derived tumors. Tumor development will be studied by light and electron microscopy in KC and brain sites using fetal rat and mouse RP. Parallel in vitro studies as well as immunocytochemistry and radioimmunoassay will also be used to monitor graft secretion and presence of specific cell types.